Discussion
The study explored the electrophysiological characteristics and
differential densities of KCa3.1 in rabbit atrium and thoracic veins. We
offer evidence that (1) the expression of KCa3.1 is higher in the PVs
and SVC than in the RA and LA; (2) DAD and DAD-induced triggered
activity was induced in the PVs and SVC but not in the RA or LA by
electrical stimulation in the presence of isoproterenol and high
calcium. The KCa3.1 inhibitor TRAM-34 inhibited DAD and DAD-induced
triggered activity in the PVs and SVC. (3) EAD was induced in the PVs
and SVC but not in the RA or LA by electrical stimulation in the
presence of acetylcholine and high calcium. The KCa3.1 inhibitor TRAM-34
inhibited EAD in the PVs and SVC.
The thoracic veins such as PVs and SVC are important foci for ectopic
atrial tachycardia and AF. The PVs cause approximately 70% cases of AF,
while SVC as second most important thoracic vein for AF, causes
5.3-12.8% AF.2 It can be easily elicited 3 phase EAD
and DAD trigger activity in PVs, SVC preparations by parasympathetic or
sympathetic nerve stimulation which indicate that automaticity and
trigger activity are related to calcium regulation. 3The mechanism of increased PVs and SVC automaticity remains unclear.
Specialized cardiac cells associated with pacemakers, such as P-like and
Purkinje cells, have been observed in the PVs and SVC of rats, dogs and
humans.12 Cardiac developmental studies have shown
that PVs, SVC and sinoatrial nodes originate from venous sinuses rather
than cardiac progenitor cells. Researchers have found that these sites
are prone to spontaneous electrical activity and that automaticity is
significantly increased.13 Studies have shown that
KCa3.1 is expressed in the human atrium but is absent in
the ventricle, and KCa3.1 is also expressed in the PVs
of dogs and rabbits.14,15In the present study, we
found that the distribution of KCa3.1 in the heart is
heterogeneous and is high in the PVs and SVC but low in the RA and LA.
Furthermore, the expression of KCa3.1 was significantly
higher in the PVs than in the SVC.
KCa3.1 plays an important role in the automaticity in
human embryonic stem cells by shaping diastolic slope during diastolic
afterdepolarization. KCa3.1 inhibitor not only
significantly decrease or even stop the automaticity of human embryonic
stem cell-derived cardiomyocytes but also reduce the sinoatrial node
firing rate.8 It has been recognized that DAD and late
3 phasic early afterdepolarization (EAD) in the thoracic vein are the
underlying mechanisms of ectopy initialed AF.3Previous study shows that iPSCs derived cardiomyocytes from
catecholamin-sensitive ventricular tachycardia patient have more
KCa3.1 expressed compared to cardiomyocytes from the
normal person, which make it more vulnerable to DAD-induced trigger
activity under isoproterenol super-fused. Blockade
KCa3.1 by TRAM-34 eliminated the DAD-induced trigger
activity.9 In our study, DAD and DAD-induced triggered
activity was easily elicited in the PVs and SVC but not in the RA and
LA. 5uM TRAM-34 eliminated the DAD-induced triggered activity by
selectively blockading KCa3.1. Sympathetic activation
increases cardiac calcium entry and spontaneous sarcoplasmic reticulum
calcium release, which eventually produces local increases in cytosolic
Ca2+ that extrudes via the
Na+-Ca2+ exchanger generating
cellular depolarization, with DAD, which triggers premature beats and
tachyarrhythmia.16 Previous study has shown that after
left atrial volume overload, the action potential duration in the
pulmonary vein was shortened by the activation of
KCa3.1.15 From our previous studies,
after 7 h pacing, KCa3.1 is significantly higher in the
atrium than the control group. Injection of TRAM-34 could terminate AF
and decrease the heart rates. 5 All the evidence above
indicates that KCa3.1 is essential for automaticity and
trigger activity in PVs and SVC by influencing the DADs and calcium
transient.